It has been known since long that different cannabinoids, which are the major active constituents of the plant Cannabis sativa (cannabis), have pharmacological activity. Well-known examples of such cannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD).
THC is known to have mild to moderate analgesic effects and can for example be used to alleviate neuropathic pain and spasticity in patients suffering from multiple sclerosis (MS). Other known effects of THC include relaxation, alteration of visual, auditory, and olfactory senses, and appetite stimulation. However, THC is also known to be a psychomimetic component which has been shown to elevate levels of anxiety and psychotic symptoms in healthy individuals.
Bioavailability of pharmaceutical substances taken perorally depends, first of all, on the extent to which the pharmaceutically active substance is absorbed from the intestinal environment across the intestinal mucosa. Lipophilic pharmaceutical substances such as THC are generally poorly absorbed from the intestinal environment, inter alia because of their poor solubility and/or dispersibility in water.
Bioavailability of a pharmaceutical substance taken perorally furthermore depends on the susceptibility of the substance to the so-called first pass effect. Substances absorbed from the intestine, before being distributed throughout the body, have to pass the liver first where they may be metabolized immediately. THC is generally assumed to be rather susceptible to first-pass metabolization.
THC oral absorption is slow and unpredictable, with peak concentrations occurring 1-5 hours post dose. Plasma THC maximum concentrations of 4.4-11.0 μg/L can be achieved after a 20 mg dose of oral THC (Ohlsson et al., Plasma delta-9-tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther 1980; 28: 409-16). THC bioavailability is approximately 6% when orally administered, compared to up to 27% when inhaled (Ohlsson et al., Single dose kinetics of deuterium labelled delta-1-tetrahydrocannabinol in heavy and light cannabis users. Biomed Environ Mass Spectrom 1982; 9: 6-10).
In view of THC's low oral bioavailability, over the years considerable effort has been put into the development of pharmaceutical delivery systems for alternative routes of administration, such as buccal, sublingual, pulmonal, nasal and rectal administration.
It is also well established that THC is a highly unstable drug. Hence, another important aspect for the formulation of THC dosage forms is to overcome the stability problem. THC is particularly sensitive to oxidation. Presence of cannabinol (CBN), the thermo-oxidative degradation product of THC, in the material is indicative of THC degradation by oxidation. Munjal et al. (Polymeric Systems for Amorphous Δ9-Tetrahydrocannabinol Produced by a Hot-Melt Method. Part II: Effect of Oxidation Mechanisms and Chemical Interactions on Stability, J Pharm Sci. 2006 November; 95(11): 2473-2485) describe the outcome of investigations that aimed to elucidate the mechanism for the oxidative degradation of THC in polymer matrix systems prepared by a hot-melt fabrication procedure, and to study the potential for controlling these mechanisms to reduce the degradation of THC in solid dosage formulations.
THC-containing dosage units for oral administration have been described in some patent publications.
WO 95/025504 describes a pharmaceutical preparation comprising a stable emulsion of a pharmaceutical agent incorporated into a hydrophobic emulsion of a long chain carboxylic acid, long chain carboxylic acid ester, long chain carboxylic acid alcohol and mixtures thereof in a dosage form suitable for oral delivery.
WO 02/064109 describes a pharmaceutical formulation for use in administration of a lipophilic medicament via a mucosal surface, which formulation comprises at least one lipophilic medicament and at least one self emulsifying agent. Example 6 of the patent application describes the preparation of a tablet for buccal or sublingual administration by dissolving glyceryl monostearate, polysorbate 80, ascorbyl palmitate and α-tocopherol and THC in alcohol, spraying the alcoholic solution onto a powder mix consisting of lactose and soluble starch, evaporating the alcohol, dusting the resulting granulate with talc and compressing to a target tablet weight of 101 mg.
WO 2006/063109 describes a stabilized oral dosage form of a cannabinoid, comprising a mixture of a therapeutically effective amount of a cannabinoid dispersed in an oil-based carrier contained in unit dosage form selected from a hard gelatin capsule, a cellulosic capsule, a starch capsule, and a non-animal based hydrocolloid film-forming composition.
WO 2006/133941 describes a dosage form comprising a therapeutically effective amount of crystalline THC and a pharmaceutically-acceptable carrier, which dosage unit is adapted for oral administration, parenteral administration, transmucosal administration, transdermal administration, or administration by inhalation.
WO 2008/033023 describes a granulate having a volume weighted mean diameter of 1-200 μm and containing:                at least 0.1 wt. % of a pharmaceutically active substance, such as cannabinoids;        at least 10 wt. % of emulsifier, such as sucrose fatty acid ester; and        0-89.9 wt. % of a water-dispersible saccharide; the combination of the pharmaceutically active substance, the emulsifier and the water-dispersible saccharide together representing at least 60 wt. % of the granulate;wherein the granulate is monophasic or wherein the granulate comprises a dispersed phase containing the pharmaceutically active substance, said dispersed phase having a volume weighted mean diameter of less than 300 nm. Example 8 describes the preparation of a tabletting powder containing 5 g of a microgranulate and 17 g of other components including 5 g of lactose, the microgranulate being composed of tetrahydrocannabinol and sucrose monolaurate (1:15). The tabletting powder is compressed into tablets of 60 mg.        
WO 2008/033024 describes dosage units for sublingual, buccal or oral administration of water-insoluble pharmaceutically active substances. Example 1 describes the preparation of a monophasic microgranulate consisting of THC and sucrose monolaurate in a weight ratio of 1:15 using a dry granulation process. Example 3 of this patent application describes the manufacture of a tabletting powder for direct compression using 5 g of the microgranulate obtained from Example 1 and 17 g of other components including 5 g of lactose and the compression to 7 mm tablets with a total weight of 60 mg.
WO 2009/020666 describes a stabilized cannabinoid formulation suitable for oral administration, comprising a cannabinoid in a semi-aqueous solution buffered to a pH of 5 to 10, the solution comprising water and an organic cosolvent to maintain the physical stability of the formulation.
WO 2012/033478 describes an oral dosage form of cannabinoids in a self-emulsifying system operable to avoid hepatic first pass metabolism, said oral dosage form comprising:                1-90 wt % of a pharmacologically active form of cannabinoids;        15-85 wt % of one or more triglycerides;        15-85 wt % of one or more mixed glycerides; and        5-90 wt % of a surfactant which promotes self-emulsification.        
It is an object of the invention to provide a dosage unit for peroral administration of THC that combines excellent (oxidative) stability with high and predictable bioavailability.